The demonstrated success of colorectal cancer (CRC) screening in randomized clinical trials (RCT), including the PLCO Trial, has spurred increased use of colonoscopy, which is the preferred primary means of screening in the U.S. Although screening has contributed to recent declines in CRC incidence and mortality, the increasing utilization of colonoscopy poses new clinical challenges. First, an estimated 8-15% of CRC arise within 5 years of a colonoscopy without detection of neoplasia (negative colonoscopy) or after all visible neoplasia has been eradicated. As the proportion of the population undergoing colonoscopy rises, these tumors, known as interval CRC, will comprise a greater burden of overall CRC. Although some interval CRCs may be due to suboptimal endoscopic technique, a substantial portion likely develops due to differences in biology compared to typical CRCs. Second, the increase in colonoscopy utilization and resulting detection of adenomas, the acknowledged precursor of most CRC, will stimulate increasing use of surveillance colonoscopy, or repeated colonoscopic monitoring of subjects for recurrent adenomas. However, surveillance colonoscopy is often improperly applied in clinical practice, with higher risk subjects undergoing delayed surveillance, and lower risk subjects undergoing excessive testing. A glaring problem in properly tailoring surveillance to risk is that current guidelines are blunt and expansive, supported by largely empirical evidence based on pathologic classifications established decades ago. Thus, novel approaches to improve risk stratification of individuals after resection of adenoma for colonoscopic surveillance is a highly significant unmet need. Fortunately, recent efforts such as The Cancer Genome Atlas (TCGA) study have vastly expanded our understanding of the genomic and molecular features of CRC and have laid the foundation for addressing these new clinical challenges. Our overarching hypothesis is that characterization of genomic features of incident resected adenomas using a panel of TCGA-identified CRC-mutations as well as novel alterations associated with interval CRC can better assess recurrence risk and stratify patients for optimal endoscopic follow-up. To address this hypothesis, we propose to conduct, using the unique tissue resources of the PLCO Trial, whole exome sequencing (WES) of CRCs to comprehensively identify specific somatic genomic alterations associated with interval as opposed to screen-detected CRC. These alterations, combined with more standard, previously identified molecular abnormalities associated with CRC, will be queried in adenomas to determine their association with adenoma recurrence and improve tailoring of colonoscopic surveillance intervals. Identification of genetic alterations associated with interval CRC and recurrence of adenoma may provide new insights into how to more effectively prevent interval CRC through improved risk stratification for colonoscopy and inform our understanding of pathways fundamental to tumor morphology and progression.